Activation of LXR increases acyl-CoA synthetase activity through direct regulation of ACSL3 in human placental trophoblast cells

Asim K. Duttaroy,M. Susanne Weedon-Fekjaer,Knut Tomas Dalen,Hilde Irene Nebb,Karianne Solaas,Anne Cathrine Staff

doi:10.1194/jlr.m004978

Asim K. Duttaroy, M. Susanne Weedon-Fekjaer + Show 4 more

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https://doi.org/10.1194/jlr.m004978

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Abstract

Placental fatty acid transport and metabolism are important for proper growth and development of the feto-placental unit. The nuclear receptors, liver X receptors alpha and beta (LXRalpha and LXRbeta), are key regulators of lipid metabolism in many tissues, but little is known about their role in fatty acid transport and metabolism in placenta. The current study investigates the LXR-mediated regulation of long-chain acyl-CoA synthetase 3 (ACSL3) and its functions in human placental trophoblast cells. We demonstrate that activation of LXR increases ACSL3 expression, acyl-CoA synthetase activity, and fatty acid uptake in human tropholast cells. Silencing of ACSL3 in these cells attenuates the LXR-mediated increase in acyl-CoA synthetase activity. Furthermore, we show that ACSL3 is directly regulated by LXR through a conserved LXR responsive element in the ACSL3 promoter. Our results suggest that LXR plays a regulatory role in fatty acid metabolism by direct regulation of ACSL3 in human placental trophoblast cells.

Highlights

Placental fatty acid transport and metabolism are important for proper growth and development of the fetoplacental unit
We report that ligand activation of liver X receptor (LXR) stimulates acyl-CoA synthetase activity and fatty acid uptake through increased ACSL3 expression in these cells
As ACSL3 was shown to affect the fatty acid uptake, we investigated if the LXR-mediated increase in ACSL3 expression and total acyl-CoA synthetase activity increased the fatty acid uptake in human placental choriocarcinoma (BeWo) cells

Summary

Introduction

Placental fatty acid transport and metabolism are important for proper growth and development of the fetoplacental unit. The nuclear receptors, liver X receptors ␣ and ␤ (LXR␣ and LXR␤), are key regulators of lipid metabolism in many tissues, but little is known about their role in fatty acid transport and metabolism in placenta. The current study investigates the LXR-mediated regulation of longchain acyl-CoA synthetase 3 (ACSL3) and its functions in human placental trophoblast cells. We demonstrate that activation of LXR increases ACSL3 expression, acyl-CoA synthetase activity, and fatty acid uptake in human tropholast cells. Silencing of ACSL3 in these cells attenuates the LXRmediated increase in acyl-CoA synthetase activity. Our results suggest that LXR plays a regulatory role in fatty acid metabolism by direct regulation of ACSL3 in human placental trophoblast cells.—Weedon-Fekjaer, M. Activation of LXR increases acyl-CoA synthetase activity through direct regulation of ACSL3 in human placental trophoblast cells.

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